The Sickle Cell Center at Georgia Health Sciences University has a long-standing history of excellence in hemoglobinopathies research, particularly in the area of sickle cell disease. This funding opportunity brings together a group of distinguished researchers in the fields of sickle cell disease (basic, clinical, and translational), endothelin, basic research in kidney disease, studies in a mouse model of sickle cell disease (SCD), and pain research. The goal of this project is tripartite: 1) To study the role of endothelin-1 in SCD with regards to inflammation, vasculopathy, lung and kidney injury, and pain; 2) To train new investigators in multidisciplinary research activities in sickle cell disease and promote research interest in high school students through a summer student program; 3) To provide administrative and informatics infrastructure for the centers funded through this initiative. To achieve these goals, a multidisciplinary team of experts has been assembled to identify the role of endothelin-1 in SC. The role of endothelin-1 in the pathogenesis of vasculopathy, inflammation, organ damage, and pain and nociception will be studied in a transgenic mouse model of SCD. In Years 4 and 5 of this project, a small pilot clinical trial will be initiated to study safety and efficacy of an ETA receptor blockade on inflammation, pain, nociception, and the progression of sickle nephropathy and on microvascular blood flow and pulmonary arterial circulation in adults with SCD. The Translational Research Skills Development Core will train early stage investigators how to conduct high impact, multidisciplinary, translational, hemoglobinopathy research. This core will also train scholars to write competitive K or ROI grants to support transition to independent translational research careers. The Administrative Coordinating Center will provide support for the administrative and coordinating activities and create and maintain the informatics infrastructure necessary to support the activities of the EHRA program.